Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV- associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. One of the explanations could be constant compromise of blood brain barrier (BBB) driven by chronic inflammatory responses documented in HIV-infected individuals even with well-controlled virus replication yet with HAND progression. Chronic neuroimmune activation is present in ART-treated patients as indicated by elevated levels of soluble inflammatory factors in the cerebrospinal fluid and blood. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. BBB dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury has been documented in animal models of diabetes showing memory deficits and was associated with dysfunction of brain pericytes supporting endothelial cells. Taking together clinical and experimental data, BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. We propose that cognitive impairment in HIV- infected individuals is mediated by BBB injury that is further aggravated by metabolic alterations associated with DM causing HAND. Preliminary data support this idea showing elevated glucose levels correlated with increased BBB permeability, cognitive impairment, microglia activation and loss of pericytes in animal models for DM types 1 and 2. We found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules after exposure to HIV and DM-relevant stimuli. We hypothesize that prevention of BBB compromise in DM/HIV will diminish neurocognitive decline independently of tight glucose control. We will identify biomarkers of such BBB injury, correlate with barrier damage and cognitive decline, define signaling pathways associated with BBB injury in DM/HIV and test novel treatment approaches. We will study the contribution of DM- and HIV- mimicking conditions on cognition and BBB injury in cross-validating experiments using well- established in vitro systems (co-culture of human primary brain microvascular endothelial cells/primary human brain pericytes), functional assays, animal models of DM types 1 and 2 combined with HIV brain exposure and `humanized' NSG mice with chronic HIV infection and diabetes. Results of such studies will open opportunities for very much needed individualized treatment for HAND.